JPS63112515A - Spray dried acetaminophen - Google Patents

Abstract

A therapeutic taste-neutral powder form of acetaminophen is obtained by spray-drying a suspension of colloidal silica in a lower alkanol solution of acetaminophen and ethyl cellulose. The powder can be formulated into fast dissolving dosage forms, chewable tablets and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the Σζ law, for example: 1' U.S. Pat. No. 4,305,502
No. 4,371,516 and British Patent Specification No. 1,548,022, a new therapeutic form of tasteless spray-dried Regarding acetaminophen.

More particularly, the present invention relates to a spray-dried powder produced by spray-drying a solution of acetaminophen and ethylcellulose in a low alkanol in which colloidal silica is suspended. The spray dried powder is tasteless. "Tasteless" means that the powder is essentially tasteless and neither sweet nor bitter.

BACKGROUND OF THE INVENTION Acetaminophen (also known as valacetamol) is widely used as an analgesic and antipyretic;
It is not palatable enough to be used in chewable tablets for people who cannot swallow solid dosage forms whole.

Flavors such as chocolate, banana, orange, lemon, licorice, root beer and raspberry have been proposed especially for bitter-tasting drugs. These flavors are not reliable masking ingredients. Mint flavor is useful in improving the chalky taste characteristics. However, bitterness properties are very difficult to mask to a large extent, especially when the flavor does not resemble the expected native taste.

When considering oral acceptance of chewable tablets or chewable tablets, other characteristics, including mouthfeel, need to be addressed.

U.S. Patent Nos. 4,305,502 and 4.371.
The rapidly dissolving dosage forms described in No. 516 and British Patent No. 1.54.8,022 are manufactured in such a way that they disintegrate in water within 10 seconds, for example within 5 seconds, so that saliva in the oral cavity Dissolves quickly. Such oral dosage forms may consist of a network of pharmaceutically acceptable water-soluble or water-dispersible carrier materials (e.g. gelatin) carrying a unit dose of the drug substance; is 10
The carrier material is inert to the drug substance such that it can be disintegrated in water within seconds and the network removes the solvent from a solid state composition consisting of the drug substance and a solution of the carrier material in a solvent. Obtained by sublimation. Traditionally, the use of such dosage forms has been limited to medicinal products that are tasteless or have a slight unpleasant taste that can be masked by flavoring. However, pharmaceuticals with a bitter taste, such as acetaminophen, have not heretofore been able to be used in such dosage forms.

DISCLOSURE OF THE INVENTION In accordance with the present invention, there is provided a novel therapeutic spray-dried acetaminophen in the form of a tasteless powder that can be formulated into chewable tablets and the like. The powder is produced by spray drying a solution of acetaminophen and ethyl cellulose in a low alkanol in which colloidal silica is suspended.

Preferably, the lower alkanol is ethanol.

The present invention particularly provides about .10 to 70
IIJ of colloidal silica in a low alkanol solution of acetaminophen and ethyl cellulose, wherein the powder is comprised of % by weight acetaminophen, about 15-30% by weight ethylcellulose and about 15-30% by weight colloidal silica; The present invention provides spray-dried acetaminophen in the form of a therapeutic powder that is spray-dried from Solution E.

According to another aspect of the invention, the dosage form is
A solid pharmaceutical dosage form for oral administration is provided which can be disintegrated within 0 seconds and comprises the drug formulated into spray-dried acetaminophen in the form of a tasteless powder of the present invention.

Acetaminophen useful in the present invention may be of pharmaceutical grade. Ethylcellulose useful in the present invention may also be international formulation or pharmaceutical grade. Suitable grades include Dow Chemical Company Mittland Pot Michigan (Dow C1+e
mical Company.

M1dland Michigan) and Bercules, Inc., Wilmington Plowea (
1-1ercuIes, Inc, of Wilmi
ngton, Delaware).

Colloidal silica useful in the present invention has a particle size of about 10 microns. Suitable grades are Cabot Corporation of Boston, Mazachusetts
bot Corporation ofI3ost
Carbosil-M-5, marketed by Carbosil, Massachusetts,
and BQ Company, Philadelphia;
Bennruvenia (PQ Company, Ph1l
adelphia.

P ennsylvania).

The weight percent of acetaminophen in the powder can range from about 40 to 70 weight percent, and the weight percent of ethylcellulose can range from about 15 to 30 weight percent. Ethyl cellulose has a slight bitterness in the 15-fold nail shape, but 20%
Above this, the powder is tasteless. The weight percent of colloidal silica in the powder can be about 15-30 weight percent.

The solvent for ethylcellulose can be an alkanol such as methyl, ethyl, isopropyl or mixtures thereof, but must be an organic solvent in which acetaminophen is soluble. "Low alkanol" means 1 to 4
means an alkanol containing 5 carbon atoms.

To inhibit leaching of acetaminophen from the spray-dried powder, a low h1 hydrophobic material such as Himashiura can be added to the solution. A small amount of glyceryl monostearate may be added to improve taste masking.

The spray dryer can be of the conventional laboratory or commercial type. A suitable spray dryer is Buchi Laboratorium Zoo Technique Eino.
Laboratoriums-Technic AG)
, The Anhydro Company of Atrehoro,
Mazaju Sets (the A nhydr.

Company of Attleboro,
MassachuseHs) and Eco Atomizer Inc. of Columbia, Maryland (Ni
roΔomizer Inc.

of Columbia, Maryland).

The spray dryer used in the following examples was a Petit 190 type mini spray dryer. The operating conditions for the Petit mini spray dryer are customarily an inlet temperature of 220°C and an outlet temperature of 130°C.

The following examples demonstrate the production of tasteless, spray-dried acetaminophen powders of the present invention. In these examples, ethylcellulose is manufactured by Hercules Chemical Company, Wilmington, Ilercu.
les Chemical Company.

Wilmington, Delaware). The ethyl cellulose has a viscosity index of 0 and 48.
It was a standard type dry material with an ITffi of 0-495%.

The present invention will be explained in more detail with reference to the following examples.

In fact, Example 1 In this example, the feed mixture to the spray dryer consisted of the following materials:

11SP 70 7
0 85 edyl cellulose, NF +5
15 1g colloidal silica +5
15 15 ethyl alcohol -250
0m (total up to !: 1009.<100%
Stainless steel using 2600 Lightnin mixer: A
Acetaminophen was dissolved in one part of the alcohol in the container. Ethyl cellulose was dissolved in the remaining alcohol in another stainless steel mixing container 1, and then the contents of the mixing container 2) on the two sides were filtered and mixed. Colloidal silica was added and mixed until a uniform dispersion was obtained. The dispersion was then transferred to the supply popper of a Buji mini spray dryer.

During operation, the spray dryer was operated to maintain an inlet temperature of 220-225°C and an outlet temperature of 150-155°C.

The yield of spray-dried powder is approximately 90% of the theoretical yield.
Met. The product was a fine white powder, 95% of which had a particle size of 2-50 microns.

The freshly obtained product did not produce the bitter characteristics of acetaminophen when tasted. After one month of aging at room temperature, the product remained virtually acceptable with no bitter taste.

Example 2 In this example, the component amounts were changed as follows.

Ethyl cellulose, NP15 15 15
Colloidal Nrica 15 15 15
Total: 100% 100% During 1600 operation, inlet temperature 220-225°C and outlet temperature 150-1
The spray dryer was operated to maintain a temperature of 55°C.

Example 3 In this example, the component amounts were changed as follows.

USP 40 40
40 ethyl cellulose, NP30 30
30 Colloidal Silica 30 30
30 total: 100% 100% 2600 driving,
Inlet temperature 220~225℃ and exhaust outlet temperature 150~
The spray dryer was operated to maintain a temperature of 155°C.

The product obtained from the spray dryer did not taste bitter when tasted.

Example 4 In this example, isopropyl alcohol was used in place of ethyl alcohol and the feed mixture to the spray dryer consisted of the following materials:

Acetaminophen, t! SP 70 23
．． 33 Isopropyl Alcohol -200,00 Ethyl Cellulose, NF L5 5.00 Colloidal Silica 15 5.00 Isopropyl Alcohol -Adequate to 500mC Total: 100% Add acetamin to one part of the alcohol in a stainless steel mixing vessel using a lightnin mixer. Phen was dissolved. 80% of acetaminophen dissolves in 30 minutes, 9
0% dissolved after 60 minutes, then removed a small amount of residue and
Everything dissolved in time. Ethylcellulose was dissolved in a portion of alcohol in a separate stainless steel mixing vessel. Although the ethylcellulose did not dissolve even for 2 hours,
- When the device was used at night, most of it had dissolved in the morning. After mixing for 1 hour with a lightnin mixer, it was completely dissolved.

The contents of the two mixing vessels were then combined. Colloidal warping force was added and mixed until a uniform dispersion was obtained. Then, an appropriate amount of isopropyl alcohol was added to the solution up to 500 mσ. The dispersion was transferred to the supply tank of a mini spray dryer manufactured by Petit.

During operation, the spray dryer was operated to maintain an inlet temperature of 180-185°C and an outlet temperature of 113°C.

The freshly obtained white powder produced some of the bitter characteristics of acetaminophen when tasted.

Example 5 In this example, methanol was used in place of ethyl alcohol and the feed mixture to the spray dryer consisted of the following materials:

Ingredients 1500. v12@Ingredients per suspension Acetaminophen, USP 210 Ethylcellulose, NP 45 Colloidal Silica 3 Methyl Alcohol
780 U of methanol was placed in a stainless steel mixing vessel equipped with a lightnin mixer, and 210 U of acetaminophen was added.

After 1 hour of mixing, 90% of the acetaminophen was dissolved. A quantity of 690 methanol was placed in a separate stainless steel mixing vessel equipped with a light nin mixer and the speed was adjusted to produce crystallization. Ethylcellulose (45y) was then added and mixing continued for 1 hour until the ethylcellulose was dissolved.

Combine the contents of the two mixing vessels and add 1b of methanol.
An appropriate amount was added up to 00tc. Mixing continued for 1+ hour until all solids were dissolved. Next, this 500. ! ! 2
The solution of Ma1. : Introduction, I9 Koroi)・
silica was added with mixing until uniform. Glyceryl monostearate (19) was used to improve the dispersion of colloidal silica and to retain pond solids in solution.
Tegin 515) was added. The dispersion was then transferred to the supply tank of a portable spray dryer manufactured by Petit.

During the slow rotation, the spray dryer was operated to maintain an inlet temperature of 120-220°C and an outlet temperature of 78-82°C.

The freshly obtained product had a very slight bitter taste when tasted.

The particle size of the product obtained again from the spray dryer is mainly 2
~50 microns, with 50% of the product being 20
There were particle sizes smaller than microns and no particles larger than 100 microns.

The product freshly obtained from the spray dryer produced a very slight bitter taste in the mouth when tasted. The powder had a good mouthfeel as the particle size was approximately 20 microns.

EXAMPLE 6 This example describes the preparation of a dosage form II that rapidly dissolves the spray-dried, tasteless acetamide of Example 1, nophene, and the following other ingredients.

Gelatin, BY19150 4,0
10.00 Mannite, granular 3.0
7.50 Deionized water 67.10
167.75 Jewelry # 271 0.
40 1.00 Sodium lauryl sulfate 0
．． 10 0.25 Powder of Example 1 2
3.0 57.50 The above-mentioned 8-liquid batch preparation process occurs in two steps: preparation of the gelatin base and addition of the drug.

The gelatin base is prepared by adding gelatin to deionized water at 30°C and mixing until the gelatin is dissolved. The solution is then cooled to 25°C and the mannitol, sodium lauryl sulfate, sweetener and flavor added separately and dissolved.

Powdered croscarmellose (AcDisol)
Solute and tasteless spray-dried acetaminophen powder was dried and mixed and sieved through a 20 mesh screen. The '11 powder was added to the gelatin solution and mixed for 30 minutes using a homomixer to form a uniform dispersion.

In this example, the freeze dryer is a 25SRC model freeze dryer manufactured by Fildes. A fast dissolving dosage form was prepared by administering 500 nLi of a suspension of acetaminophen into thermoformed blister trays with 10 wells per tray.

Place the strainer tray into a larger tray containing the dry water-methanol mixture. Once the suspension in the wells is stable, place it on a freeze dryer tray at a storage temperature of -45°C.

When the temperature of the sample reaches 145°C, as measured by the probe in the well, turn on the condenser and turn off the freezer. The condenser temperature is -
The temperature was 40 to -45°C and the vacuum was 50 to 60 mm Torr. Then turn on the heater and keep the storage temperature at 50-55℃
Adjust to. The heat-dry cycle continues for 4 hours.

Turn off vacuum, condenser and heater and remove sample. Remove the wafers from each batch from the wells in the tray. The wafers are white and weigh 150 mg each, of which approximately 80 m9 is acetaminophen. When placed on the tongue, the wafers from each batch exhibit a cheesy/cream flavor with a very slight bitter aftertaste. When placed in water at 37°C, the wafer disintegrates within 10 seconds.

Example 7 This example describes the preparation of chewable tablets using the spray-dried unflavored acetaminophen of Example 2 and the following other ingredients.

Powder of Example 2 500mg Aluminum stearate 2mg Sorbitol
Appropriate amount total up to 700
'100mg Example 2 powder is 70% by weight or 350%
Contains mg of acetaminophen. The ingredients were mixed in a suitable mixer and formed into tablets. When the tablet was chewed in the mouth, it was tasteless and had the mouthfeel of food. The taste could be improved by formulating the tablets with a suitable flavor, such as mint flavor.

Patent Applicant: American Home Products Corporation

Claims (6)

[Claims] (1) consisting of about 40-70% by weight of acetaminophen, about 15-30% by weight of ethyl cellulose and about 15-30% by weight of colloidal silica, based on the weight of the powder, wherein the powder comprises acetaminophen and Spray-dried acetaminophen in the form of a therapeutic powder characterized in that it is spray-dried from a suspension of colloidal silica in a low alkanol solution of ethylcellulose. (2) The powder according to item (1) above, wherein the lower alkanol is ethyl alcohol. (3) consisting of about 40-70% by weight of acetaminophen, about 15-30% by weight of ethylcellulose and about 15-30% by weight of colloidal silica, based on the weight of the powder, a low alkanol of acetaminophen and ethylcellulose; A method for producing spray-dried acetaminophen in the form of a therapeutic powder, comprising spray-drying a suspension of colloidal silica in solution. (4) A solid pharmaceutical dosage form for oral administration containing the therapeutic powder form of paragraph (1) or paragraph (2) above and capable of disintegrating in water within 10 seconds. (5) consisting of a network of pharmaceutically acceptable water-soluble or water-dispersible carrier materials carrying a unit dose of a medicinal substance, said carrier material being inert to said medicinal substance;
The network is obtained by sublimation of the solvent from a solid state composition consisting of a drug substance and a solution of carrier material in a solvent, the intended solid dosage form is disintegrated in water within 10 seconds, and the drug If the substance is
) A solid pharmaceutical dosage form for oral administration, characterized in that it is a therapeutic powder form. (6) A chewable tablet containing the powder of item (1) or item (2) above.